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1.
Mol Nutr Food Res ; 68(4): e2200771, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38356045

RESUMO

SCOPE: Early diabetic retinopathy (DR) is characterized by chronic inflammation, excessive oxidative stress, and retinal microvascular damage. Syringaresinol (SYR), as a natural polyphenolic compound, has been proved to inhibit many disease progression due to its antiinflammatory and antioxidant properties. The present study focuses on exploring the effect of SYR on hyperglycemia-induced early DR as well as the underlying mechanisms. METHODS AND RESULTS: Wild-type (WT) and nuclear factor erythroid 2-related factor 2 (Nrf2)-knockout C57BL/6 mice of type 1 diabetes and high glucose (HG)-induced RF/6A cells are used as in vivo and in vitro models, respectively. This study finds that SYR protects the retinal structure and function in diabetic mice and reduces the permeability and apoptosis of HG-treated RF/6A cells. Meanwhile, SYR distinctly mitigates inflammation and oxidative stress in vivo and vitro. The retinal microvascular damages are suppressed by SYR via downregulating hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathway. Whereas, SYR-provided protective effects are diminished in Nrf2-knockout mice, indicating that SYR improves DR progression by activating Nrf2. Similarly, SYR cannot exert protective effects against HG-induced oxidative stress and endothelial injury in small interfering RNA (siRNA)-Nrf2-transfected RF/6A cells. CONCLUSION: In summary, SYR suppresses oxidative stress via activating Nrf2 antioxidant pathway, which ameliorates retinal microvascular damage by downregulating HIF-1α/VEGF, thereby alleviating early DR progression.


Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética , Furanos , Lignanas , Camundongos , Animais , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Camundongos Endogâmicos C57BL , Inflamação , Estresse Oxidativo
2.
Cardiovasc Diabetol ; 23(1): 19, 2024 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-38195474

RESUMO

AIMS: Diabetic cardiomyopathy (DCM) is a major cause of mortality in patients with diabetes, and the potential strategies for treating DCM are insufficient. Melatonin (Mel) has been shown to attenuate DCM, however, the underlying mechanism remains unclear. The role of vascular endothelial growth factor-B (VEGF-B) in DCM is little known. In present study, we aimed to investigate whether Mel alleviated DCM via regulation of VEGF-B and explored its underlying mechanisms. METHODS AND RESULTS: We found that Mel significantly alleviated cardiac dysfunction and improved autophagy of cardiomyocytes in type 1 diabetes mellitus (T1DM) induced cardiomyopathy mice. VEGF-B was highly expressed in DCM mice in comparison with normal mice, and its expression was markedly reduced after Mel treatment. Mel treatment diminished the interaction of VEGF-B and Glucose-regulated protein 78 (GRP78) and reduced the interaction of GRP78 and protein kinase RNA -like ER kinase (PERK). Furthermore, Mel increased phosphorylation of PERK and eIF2α, then up-regulated the expression of ATF4. VEGF-B-/- mice imitated the effect of Mel on wild type diabetic mice. Interestingly, injection with Recombinant adeno-associated virus serotype 9 (AAV9)-VEGF-B or administration of GSK2656157 (GSK), an inhibitor of phosphorylated PERK abolished the protective effect of Mel on DCM. Furthermore, rapamycin, an autophagy agonist displayed similar effect with Mel treatment; while 3-Methyladenine (3-MA), an autophagy inhibitor neutralized the effect of Mel on high glucose-treated neonatal rat ventricular myocytes. CONCLUSIONS: These results demonstrated that Mel attenuated DCM via increasing autophagy of cardiomyocytes, and this cardio-protective effect of Mel was dependent on VEGF-B/GRP78/PERK signaling pathway.


Assuntos
Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , Melatonina , Humanos , Camundongos , Ratos , Animais , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/prevenção & controle , Miócitos Cardíacos , Fator B de Crescimento do Endotélio Vascular , Melatonina/farmacologia , Chaperona BiP do Retículo Endoplasmático , Diabetes Mellitus Experimental/tratamento farmacológico , Transdução de Sinais , Autofagia , Glucose
3.
Front Microbiol ; 14: 1141495, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36876116

RESUMO

Background: Identification of transposons without close homologs is still a difficult task. IS630/Tc1/mariner transposons, classified into a superfamily, are probably the most widespread DNA transposons in nature. Tc1/mariner transposons have been discovered in animals, plants, and filamentous fungi, however, not in yeast. Results: In the present study, we report the discovery of two intact Tc1 transposons in yeast and filamentous fungi, respectively. The first one, named Tc1-OP1 (DD40E), represents Tc1 transposons in Ogataea parapolymorpha. The second one, named Tc1-MP1 (DD34E), represents Tc1 transposons in the Rhizopodaceae and Mucoraceae families. As a homolog of Tc1-OP1 and Tc1-MP1, IS630-AB1 (DD34E) was discovered as an IS630 transposon in Acinetobacter spp. Conclusion: Tc1-OP1 is not only the first reported Tc1 transposon in yeast, but also the first reported nonclassical Tc1 transposon. Tc1-OP1 is the largest of IS630/Tc1/mariner transposons reported to date and significantly different from others. Notably, Tc1-OP1 encodes a serine-rich domain and a transposase, extending the current knowledge of Tc1 transposons. The phylogenetic relationships of Tc1-OP1, Tc1-MP1 and IS630-AB1 indicated that these transposons had evolved from a common ancestor. Tc1-OP1, Tc1-MP1 and IS630-AB1 can be used as reference sequences to facilitate the identification of IS630/Tc1/mariner transposons. More Tc1/mariner transposons will be identified in yeast, following our discovery.

4.
Cell Biol Toxicol ; 39(3): 621-639, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36640193

RESUMO

Diabetic nephropathy (DN) is one of the serious complications of diabetes that has limited treatment options. As a lytic inflammatory cell death, pyroptosis plays an important role in the pathogenesis of DN. Syringaresinol (SYR) possesses anti-inflammatory and antioxidant properties. However, the therapeutic effects and the underlying mechanism of SYR in DN remain unclear. Herein, we showed that SYR treatment ameliorated renal hypertrophy, fibrosis, mesangial expansion, glomerular basement membrane thickening, and podocyte foot process effacement in streptozotocin (STZ)-induced diabetic mice. Mechanistically, SYR prevented the abundance of pyroptosis-related proteins such as NOD-like receptor family pyrin domain containing 3 (NLRP3), cysteinyl aspartate-specific proteinase 1 (Caspase-1), and gasdermin D (GSDMD), and the biosynthesis of inflammatory cytokines interleukin 1ß (IL-1ß) and interleukin 18 (IL-18). In addition, SYR promoted the nuclear translocation of nuclear factor E2-related factor 2 (NRF2) and enhanced the downstream antioxidant enzymes heme oxygenase 1 (HO-1) and manganese superoxide dismutase (MnSOD), thereby effectively decreasing excess reactive oxygen species (ROS). Most importantly, knockout of NRF2 abolished SYR-mediated renoprotection and anti-pyroptotic activities in NRF2-KO diabetic mice. Collectively, SYR inhibited the NLRP3/Caspase-1/GSDMD pyroptosis pathway by upregulating NRF2 signaling in DN. These findings suggested that SYR may be promising a therapeutic option for DN.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Camundongos , Animais , Nefropatias Diabéticas/tratamento farmacológico , Antioxidantes/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Piroptose , Caspases
5.
Int Immunopharmacol ; 112: 109245, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36150227

RESUMO

Photoreceptor degeneration is a principal event in a variety of human retinal diseases. Progressive apoptosis of photoreceptors leads to impaired vision and blindness, for which there is no curative treatment. Adenosine 2A receptors (A2AR) are expressed in microglia. Blockade of A2AR has been shown to protect neurons via suppression of inflammation. However, the therapeutic effects of A2AR antagonists on photoreceptor degeneration have not been characterized. In this study, adult zebrafish were exposed to short term high-intensity light to induce photoreceptor death. SCH58261, a selective A2AR antagonist, was immediately injected into the vitreous body. Photoreceptor degeneration and microglia-induced inflammation were evaluated using immunohistochemistry, quantitative real-time polymerase chain reaction, polarization sensitive optical coherence tomography, and optomotor response. Co-culture of BV2 and 661W cells was used to investigate the interaction between microglia and photoreceptors. The results showed that A2AR was over-expressed during photoreceptor degeneration. Following intraocular SCH58261 injection, microglial activation and release of inflammatory factors were inhibited, and photoreceptor survival increased. Inactivation of microglia prevented apoptosis and autophagy in photoreceptors. Our results showed that SCH58261 intervention at the early stage of photoreceptor degeneration protected photoreceptors through inhibition of the inflammatory response, apoptosis, and autophagy.


Assuntos
Microglia , Degeneração Retiniana , Animais , Humanos , Inflamação/tratamento farmacológico , Degeneração Retiniana/tratamento farmacológico , Peixe-Zebra , Receptor A2A de Adenosina
6.
Int J Nanomedicine ; 17: 1381-1395, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35369034

RESUMO

Background: Hepatocellular carcinoma (HCC), arising from hepatocytes, is the most common primary liver cancer. It is urgent to develop novel therapeutic approaches to improve the grim prognosis of advanced HCC. 10-hydroxycamptothecin (HCPT) has good antitumor activity in cells; however, its hydrophobicity limits its application in the chemotherapy of HCC. Recently, nanoscale porphyrin metal-organic frameworks have been used as drug carriers due to their low biotoxicity and photodynamic properties. Methods: Nanoscale zirconium porphyrin metal-organic frameworks (NMOFs) were coated with arginine-glycine-aspartic acid (RGD) peptide to prepare NMOFs-RGD first. The HepG2 cell line, zebrafish embryos and larvae were used to test the biotoxicity and fluorescence imaging capability of NMOFs-RGD both in vitro and in vivo. Then, NMOFs were used as the skeleton, HCPT was assembled into the pores of NMOFs, while RGD peptide was wrapped around to synthesize a novel kind of nanocomposites, HCPT@NMOFs-RGD. The tissue distribution and chemo- and photodynamic therapeutic effects of HCPT@NMOFs-RGD were evaluated in a doxycycline-induced zebrafish HCC model and xenograft mouse model. Results: NMOFs-RGD had low biotoxicity, good biocompatibility and excellent imaging capability. In HCC-bearing zebrafish, HCPT@NMOFs-RGD were specifically enriched in the tumor by binding specifically to integrin αvß3 and led to a reduction in tumor volume. Moreover, the xenografts in mice were eliminated remarkably following HCPT@NMOFs-RGD treatment with laser irradiation, while little morphological change was found in other main organs. Conclusion: The nanocomposites HCPT@NMOFs-RGD accomplish tumor targeting and play synergistic chemo- and photodynamic therapeutic effects on HCC, offering a novel imaging-guided drug delivery and theranostic platform.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanocompostos , Fotoquimioterapia , Animais , Camptotecina/análogos & derivados , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Oligopeptídeos , Peixe-Zebra
7.
Carbohydr Polym ; 278: 118950, 2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-34973766

RESUMO

Cancer is a complex disease, and blocking tumor angiogenesis has become one of the most promising approaches in cancer therapy. Here, an exopoly heteropolysaccharide (AQP70-2B) was firstly isolated from Akebia quinata. Monosaccharide composition indicated that the AQP70-2B was composed of rhamnose, glucose, galactose, and arabinose. The backbone of AQP70-2B consisted of →1)-l-Araf, →3)-l-Araf-(1→, →5)-l-Araf-(1→, →3,5)-l-Araf-(1→, →2,5)-l-Araf-(1→, →4)-d-Glcp-(1→, →6)-d-Galp-(1→, and →1)-d-Rhap residues. Based on the close relationship between selenium and anti-tumor activity, AQP70-2B was modified with selenium to obtain selenized polysaccharide Se-AQP70-2B. Then, a series of methods for analysis and characterization, especially scanning electron microscopy coupled with energy dispersive spectrometry (SEM-EDS), indicated that Se-AQP70-2B was successfully synthesized. Furthermore, zebrafish xenografts and anti-angiogenesis experiments indicated that selenization could improve the antitumor activity by inhibiting tumor cell proliferation and migration and blocking angiogenesis.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Frutas/química , Neovascularização Patológica/tratamento farmacológico , Polissacarídeos/farmacologia , Ranunculales/química , Selênio/química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/isolamento & purificação , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Configuração de Carboidratos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/patologia , Neovascularização Patológica/patologia , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Peixe-Zebra/embriologia
8.
Carbohydr Polym ; 273: 118496, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34560937

RESUMO

A homogeneous polysaccharide, EJP90-1, was isolated from the leaves of E. japonica by hot water extraction in this study. EJP90-1 (7702 Da) was a heteropolysaccharide mainly consisting of →5)-linked-α-L-Araf-(1→, →4)-linked-ß-D-Manp-(1→, →2,4)-linked-α-L-Rhap-(1→, →4)-linked-α-D-Xylp-(1→, →4)-linked-ß-D-Galp-(1→, →2)-linked-ß-D-Galp-(1→, →6)-linked-ß-D-Glcp-(1→, α-D-Glcp-(4→, and t-linked-α-L-Araf. EJP90-1 was found to show moderate anti-tumor activity at the cellular level. In order to improve the anti-tumor activity and the potential applications of EJP90-1, a typical sodium selenite-nitric acid (Na2SeO3-HNO3) modification on EJP90-1 was carried out. X-ray photoelectron spectroscopy (XPS) and energy dispersive spectrometer (EDS) analysis confirmed that Se was successfully introduced into the polymer chain of EJP90-1. The subsequent in vitro cytotoxicity evaluation showed the selenylation modification derivative (EJP90-1-Se) possessed significant antiproliferative activity against cancer cells (HepG2 and A549 cells) through inducing cell apoptosis. The anti-tumor activity of EJP90-1-Se was further confirmed by zebrafish models, which inhibited the proliferation and migration of HepG2 cells and the angiogenesis.


Assuntos
Antineoplásicos/farmacologia , Eriobotrya/química , Neoplasias/tratamento farmacológico , Polissacarídeos/farmacologia , Selênio/química , Células A549 , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias/metabolismo , Neovascularização Patológica/metabolismo , Ácido Nítrico/química , Espectroscopia Fotoeletrônica/métodos , Folhas de Planta/química , Polissacarídeos/química , Peixe-Zebra
9.
Carbohydr Polym ; 270: 118365, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34364610

RESUMO

In this study, an inulin fructan (TMP50-2) with moderate anti-tumor activity was obtained from dandelion. To further improve the anti-tumor activity of TMP50-2, a monodisperse and stable spherical nanoparticle (Tw-TMP-SeNP, 50 nm) was fabricated. Physico-chemical analysis revealed that TMP50-2 and Tween 80 were tightly wrapped on the surface of SeNPs by forming CO⋯Se bonds or through hydrogen bonding interaction (OH⋯Se). In vitro anti-tumor assay showed that Tw-TMP-SeNP treatment could significantly inhibit the proliferation of cancer cells (HepG2, A549, and HeLa) in a dose-dependent manner, while HepG2 cells were more susceptible to Tw-TMP-SeNP with an IC50 value of 46.8 µg/mL. The apoptosis induction of HepG2 cells by Tw-TMP-SeNP was evidenced by increasing the proportion of apoptotic cells ranging from 12.5% to 27.4%. Furthermore, in vivo zebrafish model confirmed the anti-tumor activity of Tw-TMP-SeNP by inhibiting the proliferation and migration of tumor cells as well as the angiogenesis of zebrafish embryos.


Assuntos
Nanopartículas/química , Neoplasias/tratamento farmacológico , Polissacarídeos/farmacologia , Selênio/farmacologia , Taraxacum/química , Células A549 , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Frutanos/química , Frutanos/farmacologia , Células HeLa , Células Hep G2 , Humanos , Ligação de Hidrogênio , Neoplasias/metabolismo , Neoplasias/patologia , Polissacarídeos/química , Selênio/química , Peixe-Zebra
10.
Int J Biol Macromol ; 183: 90-100, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-33872613

RESUMO

A water-soluble polysaccharide identified here as ADP80-2 was acquired from Angelica dahurica. ADP80-2 was a gluco-arabinan composed of arabinose and a trace of glucose with a molecular weight of 9950 g/mol. The backbone of ADP80-2 comprised →5)-α-L-Araf-(1→, →3, 5)-α-L-Araf-(1→, →6)-α-D-Glcp-(1→, with a terminal branch α-L-Araf-(1 → residue. In terms of immunoregulatory activity, ADP80-2 can significantly promote the phagocytosis, the production of nitric oxide (NO), and the secretion of cytokines (IL-6, IL-1ß, and TNF-α) of macrophage. In addition to the cellular immunomodulatory activities, the chemokines related to immunoregulation were significantly increased in the zebrafish model after treated with ADP80-2. These biological results indicated that ADP80-2 with immunomodulatory effects was expected to be useful for the development of new immunomodulatory agents. Simultaneously, the discovery of ADP80-2 further revealed the chemical composition of A. dahurica used as a traditional Chinese medicine and spice.


Assuntos
Angelica , Fatores Imunológicos/farmacologia , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia , Angelica/química , Animais , Configuração de Carboidratos , Citocinas/metabolismo , Fatores Imunológicos/isolamento & purificação , Mediadores da Inflamação/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Fagocitose/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Polissacarídeos/isolamento & purificação , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/metabolismo
11.
Biochem Biophys Res Commun ; 551: 93-99, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33725575

RESUMO

Colony-stimulating factor 1 receptor (CSF1R) is a tyrosine kinase receptor and a key regulator of proliferation, differentiation, migration, and colonization in macrophage lineage cells. CSF1R was found to be involved in the pathogenesis of immune disorders, hematopoietic diseases, tissue damage, tumor growth and metastasis, and so on. Hence, understanding the role of CSF1R is important. CSF1R is highly conserved among vertebrates. In zebrafish, it is encoded by the colony-stimulating factor 1 receptor a (csf1ra) gene. In this study, a csf1ra-/- zebrafish mutant line was generated using clustered regularly interspaced short palindromic repeats (CRISPR)-associated 9 (CRISPR/Cas9) technology. csf1ra-/- larvae lacked the yellow cast on their heads and over their flanks, while adult mutants had poorly formed stripes. RNA-sequence analysis revealed that genes related to bile acid secretion, fat digestion and absorption, and pancreatic secretion were differentially expressed in csf1ra-/- mutants, which led to fatty changes in the liver. In addition, genes related to locomotion were also significantly changed, with the more active movement observed in csf1ra-/- larvae. Our study demonstrated that csf1ra participates in the metabolic process and behavior. This study provides new insights into csf1ra function during zebrafish development.


Assuntos
Sistemas CRISPR-Cas/genética , Locomoção/genética , Receptor de Fator Estimulador de Colônias de Macrófagos/deficiência , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Animais , Técnicas de Inativação de Genes , Larva/genética , Larva/metabolismo , Mutação , Receptor de Fator Estimulador de Colônias de Macrófagos/genética
12.
Carbohydr Polym ; 256: 117521, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33483042

RESUMO

In our continuous searching for natural active polysaccharides with immunomodulatory activity, an arabinofuranan (AQP70-3) was isolated and purified from the fruits of Akebia quinata (Houtt.) Decne. by using ion-exchange chromatography and gel permeation chromatography for the first time. AQP70-3 contained both α-l-Araf and ß-l-Araf, and the absolute molecular weight was 1.06 × 104 g/mol. The backbone of AQP70-3 comprised →5)-α-l-Araf-(1→, →3,5)-α-l-Araf-(1→, and →2,5)-α-l-Araf-(1→, with branches of →1)-ß-l-Arafand →3)-α-l-Araf-(1→ residues. Biological assay suggested that AQP70-3 can stimulate phagocytic activity and promote the levels of nitric oxide (NO), interleukin (IL)-6, IL-1ß, and tumor necrosis factor-α (TNF-α) of RAW264.7 cells. Furthermore, AQP70-3 was found to increase the production of reactive oxygen species (ROS) and NO in zebrafish embryo model.


Assuntos
Frutas/química , Fatores Imunológicos/química , Polissacarídeos/química , Ranunculales/química , Espécies Reativas de Oxigênio/agonistas , Animais , Sequência de Carboidratos , Embrião não Mamífero , Fatores Imunológicos/isolamento & purificação , Fatores Imunológicos/farmacologia , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Interleucina-6/imunologia , Interleucina-6/metabolismo , Camundongos , Peso Molecular , Óxido Nítrico/imunologia , Óxido Nítrico/metabolismo , Fagocitose/efeitos dos fármacos , Extratos Vegetais/química , Polissacarídeos/isolamento & purificação , Polissacarídeos/farmacologia , Células RAW 264.7 , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Estereoisomerismo , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Peixe-Zebra
13.
J Inflamm Res ; 13: 1043-1055, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33293848

RESUMO

BACKGROUND: The myelin sheath can be damaged by genetic and/or environmental factors, leading to demyelinating diseases, for which effective treatments are lacking. Recently, cyclooxygenase-2 (COX-2) overexpression was detected in demyelinating lesions both in patients and animal models, opening an avenue for promoting endogenous remyelination. The aim of this study was to investigate the therapeutic effect of celecoxib, a selective COX-2 inhibitor, against demyelination in a zebrafish model. METHODS: The biotoxicity of celecoxib was evaluated on zebrafish embryos. Metronidazole was used to deplete the oligodendrocytes in Tg (mbp:nfsB-egfp) transgenic fish. Celecoxib was then administered both in larvae and adults. The regeneration of the myelin sheath and the underlying mechanisms were explored by immunohistochemistry, flow cytometry, Western blot analysis, quantitative real-time polymerase chain reaction, and behavioral test. RESULTS: Celecoxib had low in vivo toxicity. A stable and practical demyelination model was established by metronidazole induction. Following celecoxib treatment, the number of oligodendrocytes was increased significantly and the concentric structure of the myelin sheath reappeared. The locomotor ability was notably improved and was close to its physiological levels. The expression of arg1, mrc1, il-10, and il-4 was upregulated, while that of il-1ß, il-12, tnf-α, il-6, caspase-3 and caspase-7 was downregulated. CONCLUSION: Inhibition of COX-2 contributed to the transformation of microglia/macrophages from the M1 to the M2 phenotype, improved the inflammatory microenvironment, and suppressed caspase-dependent apoptosis, thus exerting a therapeutic effect against demyelination.

14.
Bioorg Chem ; 104: 104331, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33142407

RESUMO

Inflammation, especially chronic inflammation, has been found to be closely related to the pathology of many diseases and the discovery of bioactive natural products to inhibit NO production is one of strategies to treat inflammation. In our continuous search for bioactive natural substances as potential anti-inflammatory agents, five new compounds (1-5) were extracted and purified from Patrinia heterophylla. The NMR and MS data analysis, along with electronic circular dichroism (ECD) calculations, led to the identification of these isolates, which were new iridoids. Using cell and zebrafish models, the in vitro and in vivo anti-inflammatory effects were conducted to evaluate the potency of anti-inflammation of these compounds. The preliminary mechanism was explored using molecular docking and Western blotting experiments.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Produtos Biológicos/farmacologia , Inflamação/tratamento farmacológico , Iridoides/farmacologia , Patrinia/química , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inflamação/metabolismo , Inflamação/patologia , Iridoides/química , Iridoides/isolamento & purificação , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Óxido Nítrico/análise , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Peixe-Zebra
15.
Carbohydr Polym ; 246: 116567, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32747240

RESUMO

In our search for bioactive polysaccharides as immunomodulatory agents, an arabinofuranan (GMP90-1) was purified and characterized from the rinds of Garcinia mangostana L. GMP90-1 (absolute molecular weight: 5.30 × 103 g/mol) was found to be composed of arabinose, galactose, and rhamnose. The backbone of GMP90-1 was determined as (1→5)-linked α-l-Araf, (1→2,3,5)-linked α-l-Araf, (1→3,5)-linked α-l-Araf, (1→6)-linked ß-d-Galp, and (1→2)-linked α-l-Rhap. Conformational analysis revealed GMP90-1 to exist as a rigid rod structure in sodium chloride solution. To explore its potential as immunomodulatory agents, an in vitro cell screening was performed and GMP90-1 was found to significantly enhance the phagocytic uptake of neutral red and improve the secreted level of nitric oxide (NO), interleukin (IL)-6, IL-1ß, and tumor necrosis factor-α (TNF-α) of macrophages. Furthermore, the cellular immunomodulatory activities were confirmed by the in vivo zebrafish experiment, which suggested that GMP90-1 with immunomodulatory effects could be considered as a potential immunomodulatory for immune diseases.


Assuntos
Garcinia mangostana/química , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polissacarídeos/química , Polissacarídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Fatores Imunológicos/isolamento & purificação , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Peso Molecular , Monossacarídeos , Óxido Nítrico/metabolismo , Extratos Vegetais/isolamento & purificação , Polissacarídeos/isolamento & purificação , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Peixe-Zebra/metabolismo
16.
Bioorg Chem ; 101: 104004, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32629274

RESUMO

Bioactive natural products play an important role in the research and development of new drugs. In our search for bioactive natural substances as potential lead compounds for inflammation, four new (1-4) and six known (6-10) triterpenoids were acquired from Lantana camara. Using NMR and MS techniques and electronic circular dichroism (ECD) calculations, these isolates were characterized and the new compounds (1-4) were found to be euphane-type triterpenoids. The in vitro anti-inflammatory effects of all the isolates were evaluated and the more bioactive compounds were selected for the investigation of preliminary mechanism using molecular docking and Western blotting experiments, as well as the in vivo anti-inflammatory evaluation using a zebrafish model.


Assuntos
Anti-Inflamatórios/farmacologia , Lantana/química , Triterpenos/farmacologia , Animais , Anti-Inflamatórios/química , Western Blotting , Linhagem Celular , Técnicas In Vitro , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Simulação de Acoplamento Molecular , Óxido Nítrico/metabolismo , Triterpenos/química , Peixe-Zebra
17.
Carbohydr Polym ; 245: 116469, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32718604

RESUMO

A novel polysaccharide (ILP50-2) was extracted, isolated and purified from the leaves of Ilex latifolia Thunb. Its structure was characterized as a repeating unit consisting of α-L-Araf-(1→, →3)-α-L-Araf-(1→, →5)-α-L-Araf-(1→, →3,5)-α-L-Araf-(1→, →2)-α-L-Rhap-(1→, →2,4)-α-L-Rhap-(1→, ß-D-Galp-(1→, →4)-ß-D-Galp-(1→, →4)-ß-D-Glcp-(1→, →6)-α-D-Manp-(1→, and →3,6)-α-D-Galp-(1→. The absolute molecular weight of ILP50-2 was 1.49 × 105 g/mol, which adapted a compact coil conformation in 0.1 M NaCl solution with Rz of 25.4 nm. Furthermore, ILP50-2 exhibited immunoregulatory activity, mainly through enhancing the phagocytosis ability of macrophages and prompting the release of nitric oxide (NO) and cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1ß (IL-1ß). Simultaneously, ILP50-2 was found to significantly increase the release of ROS and NO in zebrafish embryos, showing immunoregulatory effects in vivo.


Assuntos
Ilex/química , Fatores Imunológicos/isolamento & purificação , Fatores Imunológicos/farmacologia , Macrófagos/efeitos dos fármacos , Folhas de Planta/química , Polissacarídeos/isolamento & purificação , Polissacarídeos/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Fatores Imunológicos/química , Macrófagos/imunologia , Camundongos , Peso Molecular , Monossacarídeos , Óxido Nítrico/metabolismo , Fagocitose/efeitos dos fármacos , Polissacarídeos/química , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo
18.
Bioorg Chem ; 98: 103741, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32213364

RESUMO

A phytochemical investigation to obtain bioactive substances as lead compounds or agents for cancer led to the obtainment of six new and two known clerodane diterpenoids from the leaves of Casearia kurzii. Their structures were elucidated using NMR techniques and electronic circular dichroism (ECD) calculations. The subsequent biological cytotoxicity evaluation of these isolates toward human lung cancer A549, human cervical cancer HeLa, human chronic myeloid leukemia K562, and human hepatocellular carcinoma HepG2 was carried out. The most active compound 4 with an IC50 value of 9.7 µM against HepG2 cells was selected to examine the cytotoxic mechanism, which induced the apoptosis and arrested the HepG2 cell cycle at S stage. The in vivo zebrafish experiments revealed that compound 4 had the property of inhibiting tumor proliferation and migration.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Casearia/química , Diterpenos/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Diterpenos/química , Diterpenos/isolamento & purificação , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Folhas de Planta/química , Relação Estrutura-Atividade , Peixe-Zebra
19.
Int J Nanomedicine ; 14: 9763-9776, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31849467

RESUMO

BACKGROUND: Photoreceptor degeneration is one of the most refractory oculopathy in the world, leading to vision loss in severe cases. Methyprednisolone is one of the most commonly prescribed medications for the treatment of retinal degenerative diseases, either by oral administration or repeated intraocular injections. However, the efficacy was unsatisfactory due to its systemic or local side effects and short retention time within the retina. METHODS: Nanoscale zirconium-porphyrin metal-organic framework (NPMOF) was synthesized and characterized. The biotoxicity and imaging capability of NPMOF were evaluated using zebrafish embryos and larvae. NPMOF was then used as a skeleton and loaded with methylprednisolone (MPS) to prepare a novel kind of nanoparticle, MPS-NPMOF. Photoreceptor degeneration was induced by high-intensity light exposure in adult zebrafish. MPS-NPMOF was delivered to the injured retina by intraocular injection. The photoreceptor regeneration and its underlying mechanism were explored by immunohistochemistry, quantitative real-time polymerase chain reaction and behavioral test. RESULTS: NPMOF not only had low biotoxicity but also emitted bright fluorescence. Following a single MPS-NPMOF intraocular injection, the injured retina exhibited the faster photoreceptor regeneration with better visual function by promoting the cell proliferation. CONCLUSION: NPMOF is an ideal carrier and could be applied in tracking and delivering medications. By intraocular injection, the novel drug delivery system, MPS-NPMOF, accomplishes the sustained release of drug and plays a therapeutic role in photoreceptor degeneration.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Estruturas Metalorgânicas/química , Metilprednisolona/administração & dosagem , Porfirinas/química , Degeneração Retiniana/tratamento farmacológico , Zircônio/química , Animais , Animais Geneticamente Modificados , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Embrião não Mamífero/efeitos dos fármacos , Fluorescência , Injeções Intraoculares , Estruturas Metalorgânicas/administração & dosagem , Estruturas Metalorgânicas/farmacologia , Metilprednisolona/farmacologia , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Células Fotorreceptoras de Vertebrados/metabolismo , Retina/efeitos dos fármacos , Retina/lesões , Degeneração Retiniana/etiologia , Peixe-Zebra/embriologia
20.
Int J Nanomedicine ; 14: 57-74, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30587985

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and severely threatens human health. Since the prognosis of advanced HCC remains poor, there is an urgent need to develop new therapeutic approaches. Porphyrin metal-organic frameworks are a class of porous organic-inorganic hybrid functional materials with good biocompatibility. METHODS: Gadolinium-porphyrin metal-organic frameworks were used as a skeleton for folic acid (FA) conjugation to synthesize a novel type of nanoparticle, denoted as folic acid-nanoscale gadolinium-porphyrin metal-organic frameworks (FA-NPMOFs). The FA-NPMOFs were characterized using transmission electron microscopy, Fourier transform infrared spectroscopy and thermogravimetric-differential thermal analysis. The biotoxicity and imaging capability of the FA-NPMOFs were determined using HepG2 cells and embryonic and larval zebrafish. The delivery and photodynamic therapeutic effect of FA-NPMOFs were explored in transgenic zebrafish with doxycycline-induced HCC. RESULTS: FA-NPMOFs were spherical in structure with good dispersion and water solubility. They showed low biotoxicity, emitted bright red fluorescence, and exhibited an excellent magnetic resonance imaging capability, both in vitro and in vivo. Meanwhile, the FA-NPMOFs exhibited a strong affinity for folate receptor (FR)-expressing cells and were delivered to the tumor site in a targeted manner. Moreover, HCC tumor cells were eliminated following laser irradiation. CONCLUSION: FA-NPMOFs can be used for dual-modality imaging and photodynamic therapy in HCC and show promise for use as a carrier in new therapies for HCC and other FR-positive tumors.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Ácido Fólico/química , Ácido Fólico/uso terapêutico , Gadolínio/química , Neoplasias Hepáticas/tratamento farmacológico , Imageamento por Ressonância Magnética , Estruturas Metalorgânicas/química , Fotoquimioterapia , Animais , Carcinoma Hepatocelular/patologia , Morte Celular , Sobrevivência Celular/efeitos dos fármacos , Embrião não Mamífero/efeitos dos fármacos , Fluorescência , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Estruturas Metalorgânicas/síntese química , Nanopartículas/química , Nanopartículas/ultraestrutura , Imagem com Lapso de Tempo , Peixe-Zebra/embriologia
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